The human genome contains 4000 copies of a transposable element called LINE-1 (L1Hs). This element creates new copies of itself and inserts into and near other genes. Insertions of L1Hs into genes causes mutations and diseases such as hemophilia A and muscular dystrophy and may contribute to the development of cancer. This project focuses on the rate and mechanisms of transposition. We have found that an abnormal human chromosome found in testicular cancer enhances L1Hs expression. DNA sequence fragments that enhance L1Hs expression have been identified and are being studied in detail. We are also developing new technologies to study L1Hs that will enhance our understanding of human genetic variation. We are learning how to find differences in the locations of L1Hs in the DNA of different individuals. Retroviral vectors used for gene therapies integrate into the human cells which they infect. At present little is known about the mechanism and consequences of inserting foreign genes haphazardly into the genome; however, the evidence shown by the current project is that insertion at a site of an active gene can lead to its inactivation. In addition, it is not known what types of subtle interactions might occur between an inserted retrovirus and the endogenous human retrotransposons. Understanding the mechanisms of transposition by human endogenous transposons will advance the development of a new generation of gene therapy vectors. Individuals differ greatly in the locations of the L1Hs elements in their genomes. These differences may alter their response to environmental stimuli, including drugs and infections.